In vivo imaging method of mood disorders

Abstract

The present invention provides a method useful in the diagnosis and/or monitoring of mood disorders wherein there is an abnormal expression of PBR. The method of the invention is useful in the differential diagnosis of said mood disorders and other conditions where there is no abnormal expression of PBR but where the symptoms may be similar to those of said mood disorder.

What is claimed is: 
     
       1. A method comprising the following steps:
 (a) administering to a subject of a mood disorder characterised by abnormal expression of peripheral benzodiazepine receptors (PBR) an in vivo imaging agent of Formula I: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1-3  alkyl or C 1-3  fluoroalkyl; 
 R 2  is hydrogen, hydroxyl, halo, cyano, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  fluoroalkyl, or C 1-3  fluoroalkoxy; 
 R 3  and R 4  are independently C 1-3  alkyl, C 7-10  aralkyl, or R 3  and R 4 , together with the nitrogen to which they are attached, form a nitrogen-containing C 4-6  aliphatic ring optionally comprising 1 further heteroatom selected from nitrogen, oxygen and sulfur; 
 Y 1  is O, S, SO, SO 2  or CH 2 ; and, 
 Y 2  is CH 2 , CH 2 —CH 2 , CH(CH 3 )—CH 2  or CH 2 —CH 2 —CH 2 ; 
 and wherein Formula I as defined comprises an atom which is a radioisotope suitable for in vivo imaging; 
 (b) allowing said administered in vivo imaging agent of step (a) to bind to peripheral benzodiazepine receptors (PBR) expressed in said subject; 
 (c) detecting signals emitted by the radioisotope of said bound in vivo imaging agent of step (b) using a suitable in vivo imaging procedure; 
 (d) generating an image representative of the distribution and/or extent of said signals detected in step (c); 
 (e) determining the distribution and/or extent of PBR expression in said subject wherein said expression is directly correlated with the distribution and/or extent of said signals as represented in said image generated in step (d); and, 
 (f) using the distribution and extent of PBR expression as determined in step (e) in the diagnosis and/or monitoring of said mood disorder. 
 
     
     
       2. The method as defined in  claim 1  wherein said mood disorder is schizophrenia, panic disorder, generalised social phobia, anxiety, post-traumatic stress disorder, suicidal depression, dysthmic disorder, bipolar disorder, depression in conjunction with separation anxiety disorder, or obsessive compulsive disorder. 
     
     
       3. The method as defined in  claim 2  wherein said mood disorder is schizophrenia. 
     
     
       4. The method as defined in  claim 1  wherein said in vivo imaging agent is administered as a radiopharmaceutical composition comprising said in vivo imaging agent together with a pharmacologically-acceptable carrier. 
     
     
       5. The method as defined in  claim 1  wherein said radioisotope suitable for in vivo imaging of said in vivo imaging agent is selected from  11 C,  18 F and  123 I. 
     
     
       6. The method as defined in  claim 1  wherein R 1  of Formula I is methyl or C 2-3  fluoroalkyl. 
     
     
       7. The method as defined in  claim 1  wherein R 2  of Formula I is hydrogen, halo, C 1-3  alkoxy or C 1-3  fluoroalkoxy. 
     
     
       8. The method as defined in  claim 1  wherein R 3  and R 4  of Formula I are independently methyl, ethyl or benzyl. 
     
     
       9. The method as defined in  claim 1  wherein R 3  and R 4  of Formula I, together with the nitrogen to which they are attached, form a nitrogen-containing C 5-6  aliphatic ring. 
     
     
       10. The method as defined in  claim 1  wherein Y 1  of Formula I is CH 2 . 
     
     
       11. The method as defined in  claim 1  wherein Y 2  of Formula I is CH 2 —CH 2 . 
     
     
       12. The method as defined in  claim 1  wherein said in vivo imaging agent is of Formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2a  is hydrogen, halo or C 1-3  alkoxy; 
 R 3a  and R 4a  are independently methyl, ethyl or benzyl, or together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl ring; 
 Y 2a  is as defined in  claim 1  for Y 2 ; and; 
 n is 1, 2 or 3. 
 
     
     
       13. The method as defined in  claim 12  wherein for Formula Ia:
 R 3a  and R 4a  are both ethyl, or R 3a  is methyl and R 4a  is benzyl, or together with the nitrogen to which they are attached form an azepanyl ring; 
 R 2a  is hydrogen, methoxy or fluoro; 
 Y 2a  is CH 2 —CH 2  or CH(CH 3 )—CH 2 ; and, 
 n is 2. 
 
     
     
       14. The method as defined in  claim 13  wherein said in vivo imaging agent is of the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
       15. The method as defined in  claim 14  wherein said in vivo imaging agent is the purified enantiomer having the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
       16. The method as defined in  claim 1  which is carried out repeatedly during the course of a treatment regimen for said subject, said regimen comprising administration of a drug to combat a mood disorder. 
     
     
       17. The method as defined in  claim 16  wherein said mood disorder is schizophrenia, panic disorder, generalised social phobia, anxiety, post-traumatic stress disorder, suicidal depression, dysthmic disorder, bipolar disorder, depression in conjunction with separation anxiety disorder, or obsessive compulsive disorder. 
     
     
       18. The method as defined in  claim 17  wherein said mood disorder is schizophrenia.